CLINICAL STUDY PROTOCOL - WRHI...CLINICAL STUDY PROTOCOL A randomised, open label switch study comparing darunavir/ritonavir 400mg/100mg daily with lopinavir/ritonavir 800mg/200mg

CLINICAL STUDY PROTOCOL

A randomised, open label switch study comparing darunavir/ritonavir

400mg/100mg daily with lopinavir/ritonavir 800mg/200mg daily, in HIV-

positive participants.

PROTOCOL NO. WRHI052

Sponsor: Wits Reproductive Health and HIV Institute (Wits RHI)

Physical Address

University of the Witwatersrand

Hillbrow Health Precinct

Hugh Solomon Building

Corner Esselen Street, and Klein Street

Hillbrow, 2001

South Africa

Postal Address

University of the Witwatersrand

PO 18512

Hillbrow, 2038

South Africa

Sponsor Contact: Prof WD Francois Venter, FCP (SA)

Deputy Executive Director, Wits Reproductive Health and HIV Institute (Wits

RHI)

Associate Professor, Department of Medicine

University of the Witwatersrand, Johannesburg, South Africa

Telephone: +27 (0) 11 358 5453

Fax: +27 (0)11 358 5439

E-mail: [email protected]

www.wrhi.ac.za

Version and Date of Protocol:

Protocol Version 3.0 – 26 October 2017

CONFIDENTIAL

The concepts and information contained in this document or generated during the study are considered proprietary and may

not be disclosed in whole or in part without the expressed, written consent of

Wits Reproductive Health and HIV Institute.

The study will be conducted according to the International Conference on Harmonisation harmonised tripartite guideline

E6(R1): Good Clinical Practice.

Wits Reproductive Health and HIV Institute DRV/RTV 400/100 mg Protocol number WRHI052 Protocol Version 3.0; 26 October 2017

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Table of Contents

Protocol Approval ............................................................................................................ 5

Declaration of Investigator .............................................................................................. 6

List of Abbreviations........................................................................................................ 7

Protocol Synopsis............................................................................................................. 8

1 Introduction ..................................................................................................................11

1.1 Background Information ..................................................................................11

1.2 Current Therapy ............................................................................................... 12

1.3 Rationale .......................................................................................................... 13

1.4 Other Study Medications ................................................................................. 15

2 Study Objectives ......................................................................................................... 15

2.1 Primary Objective ............................................................................................ 15

2.2 Secondary Objective ........................................................................................ 15

3 Study Design ............................................................................................................... 15

4 Selection of Study Population ..................................................................................... 16

4.1 Inclusion Criteria ............................................................................................. 17

4.2 Exclusion Criteria: ........................................................................................... 17

5 Study Procedures ........................................................................................................ 18

5.1 Screening: ........................................................................................................ 18

5.2 Enrolment: ....................................................................................................... 18

5.3 Follow-up visit procedure: .............................................................................. 19

5.4 Efficacy Assessments ...................................................................................... 19

5.5 Early withdrawal ............................................................................................. 20

5.6 Replacements ................................................................................................... 20

6 Safety Assessments ..................................................................................................... 20

6.1 Adverse Events ................................................................................................ 20

6.2 Serious Adverse Events ................................................................................... 21

6.3 Assessment of AEs .......................................................................................... 22

6.5 Management of Pregnancy .............................................................................. 22

6.6 Physical Examination and Vital Sign Measurements ...................................... 23


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7 Study Treatments ........................................................................................................ 23

7.1 Medication Supplies ........................................................................................ 24

7.2 Study Medication Accountability .................................................................... 25

7.3 Prior, Concomitant and Subsequent Therapy .................................................. 25

7.4 Process for Antiretroviral Switch .................................................................... 25

7.5 Post-trial access to darunavir 400mg ............................................................... 26

8 Statistical Analysis Plans ............................................................................................ 26

8.1 Primary Efficacy Endpoint .............................................................................. 26

8.2 Secondary Efficacy Endpoints......................................................................... 26

8.3 Safety Endpoints .............................................................................................. 26

8.4 Sample Size Calculations ................................................................................ 26

8.5 Analysis Sets .................................................................................................... 27

8.6 Statistical Analysis ........................................................................................... 27

8.7 Primary Efficacy Analysis ............................................................................... 28

8.9 Safety Analyses ............................................................................................... 28

8.10 Interim Analyses ............................................................................................ 29

9 Data Management ....................................................................................................... 29

10 Other study Activities ............................................................................................... 30

10.1 Confidentiality ............................................................................................... 30

10.2 Reporting ....................................................................................................... 30

10.3 Investigator Documentation .......................................................................... 30

10.4 Monitoring of the Study ................................................................................ 31

10.5 Protocol Amendments ................................................................................... 31

10.6 Protocol Violations and Deviations ............................................................... 31

10.7 Inspection of Records .................................................................................... 32

10.8 Records Retention ......................................................................................... 32

10.9 Study Termination ......................................................................................... 32

10.10 Publications ................................................................................................. 32

11 Appendix: Schedule of Events .................................................................................. 33

12 Reference List ........................................................................................................... 35


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List of Tables

Table 1 Treatment Regimen ........................................................................................... 16

Table 2 Study Medication Supplies ............................................................................... 24

Table 3 Schedule of Events ............................................................................................ 33

Table 4 Schedule of Post-Trial Access ........................................................................... 34

List of Figures

Figure 1 Study design .................................................................................................... 16


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Protocol Approval

Study Title A randomised, open label switch study comparing

darunavir/ritonavir 400mg/100mg daily with lopinavir/ritonavir

800mg/200mg daily, in HIV-positive participants.

Protocol

Number

WRHI052

Protocol Date Protocol Version 3.0 – 26 October 2017

Protocol accepted and approved by:

Principal Investigator

Prof WD Francois Venter, FCP (SA)

Deputy Executive Director, Wits RHI

Associate Professor, Department of Medicine

University of the Witwatersrand, Johannesburg, South Africa


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Declaration of Investigator

I have read and understand all sections of the protocol entitled “A randomised, open

label switch study comparing darunavir/ritonavir 400mg/100mg daily with

lopinavir/ritonavir 800mg/200mg daily, in HIV-positive participants” and the

accompanying current information for investigators.

I agree to supervise all aspects of the protocol and to conduct the clinical investigation

in accordance with the Protocol Version 3.0, dated 26 October 2017, the International

Conference on Harmonisation harmonised tripartite guideline E6 (R1): Good Clinical

Practice, and all applicable government regulations. I will not implement protocol

changes without HREC approval except to eliminate an immediate risk to participants.

I agree to administer study treatment only to participants under my personal

supervision or the supervision of a subinvestigator.

I will not supply the investigational drug to any person not authorised to receive it.

Confidentiality will be protected. Participant identity will not be disclosed to third

parties or appear in any study reports or publications without the permission of the

participant.

___________________________ 26 Oct 2017

Signature of Principal Investigator Date

Prof. WD Francois Venter .

Printed Name of Principal Investigator


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List of Abbreviations

Abbreviation Definition

ADR adverse drug reaction

AE adverse event

ART antiretroviral therapy

BID twice daily

CYP cytochrome P450

DRV darunavir

DRV/r ritonavir-boosted darunavir

DSMB data and safety monitoring board

GCP Good Clinical Practice

HIV human immunodeficiency virus

HREC Wits Human Research Ethics Committee

ICF informed consent form

ICH International Conference on Harmonisation

LPV/r ritonavir-boosted lopinavir

NNRTI non-nucleoside reverse transcriptase inhibitor

NRTI nucleoside reverse transcriptase inhibitor

N(t)RTI nucleoside/nucleotide reverse transcriptase inhibitor

PP per protocol

SAE serious adverse event

SAP statistical analysis plan

Wits RHI Wits Reproductive Health and HIV Institute

WHO World Health Organisation


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Protocol Synopsis

Protocol Number: WRHI052

Title: A randomised, open label switch study comparing darunavir/ ritonavir 400mg/100mg daily with

lopinavir/ ritonavir 800mg/200mg daily, in HIV-positive participants.

Study Phase: Phase 3b

Study Sites: Single-centre, South Africa

Objectives: The primary objective of this study is to assess the non-inferiority of DRV/r 400mg/100mg daily

when compared with LPV/r total dose 800mg/200mg daily, in combination with a nucleoside backbone, as

determined by the proportion of participants on each regimen with undetectable plasma HIV-1 RNA levels (<50

copies/mL) at week 48.

The secondary objective of this study is to assess the tolerability and safety of low dose DRV/r when switching

from LPV/r, over 48 weeks, using standard of care participant symptom report and laboratory measures.

Participant Population: HIV-1 infected male or female participants on a lopinavir-containing ART regimen,

with plasma HIV-1 RNA levels <50 copies/mL, will be considered for enrolment in the study if they meet all of

the inclusion criteria and none of the exclusion criteria.

Inclusion Criteria: Each participant must meet all of the following criteria to be enrolled in this study:

1. Participant is aged ≥18 years

2. Participant weight >40kg

3. Participant is on a LPV/r-containing regimen for at least 6 months with no history of other protease

inhibitors

4. Participant has a plasma HIV-1 RNA level <50 copies/mL in the last 60 days

5. Participant is informed and has the ability to comprehend the full nature and purpose of the study, and

give voluntary written informed consent before inclusion in the study

Exclusion Criteria: Participants meeting any of the following criteria will be excluded from the study:

1. Participants who are taking any antiretrovirals other than nucleoside/nucleotide reverse transcriptase

inhibitors and LPV/r

2. Any prior history of genotype-documented protease inhibitor resistance

3. Participants who are taking rifampicin or any other therapy with major cytochrome P450 interactions,

within the last month

4. Participants who are allergic to sulphonamides

5. Participants who have a current history of drug or alcohol abuse that, in the opinion of the investigator,

may be an impediment to participant adherence to the protocol

6. Female participants who are currently pregnant or breastfeeding

7. Female participants desiring pregnancy during the next year

8. Participants who have a strong likelihood of relocating far enough to make access to the study site

difficult

9. Any condition(s) or laboratory report that, in the opinion of the investigator, might put the participant

at risk, or interfere with the study objectives or the participant’s adherence to study requirements

Study Design

This is an open label, randomised, parallel-group, phase 3b, single-site switch study. The purpose of the study is

to demonstrate non-inferiority of low-dose DRV/r 400/100 mg once daily compared with LPV/r 800/200mg

when administered over 48 weeks in combination with two nucleos(t)ide reverse transcriptase inhibitors in

participants infected with HIV-1. These participants are already virologically suppressed and stable on a

standard second-line regimen. All medications will be provided in an open-label design.

Approximately three hundred male and female participants infected with HIV-1 on standard second-line therapy

with LPV/r, with plasma HIV-1 RNA levels <50 copies/mL, will be randomly assigned in a 1:1 ratio

(approximately 150 participants per treatment group) to Treatment Group 1 (DRV/r + 2 N(t)RTIs) or Treatment

Group 2 (LPV/r + 2 N(t)RTIs).

The study includes screening and enrolment visits, 5 follow-up visits from Week 4 to Week 48, with Week 48

being an end-of-study (EOS) visit.


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Screening: Screening will take place between Days –60 and –1, prior to the first study treatment administration.

Within the 60-day period re-screenings may be done to confirm eligibility.

Enrolment: At enrolment participants who meet all inclusion criteria and none of the exclusion criteria will be

enrolled in the study, given a participant number, randomly assigned to either Treatment Group 1 or Treatment

Group 2, and provided with open label study medication. There will be no laboratory assessments at enrolment

if the necessary assessments were completed at the screening visit.

Treatment Period: Participants will return to the site at pre-defined time intervals for clinical assessments and

blood sampling. At all visits, participants will be questioned about concomitant medications and adverse events

(AEs) to assess their wellbeing.

Interim Analysis: A data safety monitoring board (DSMB) will monitor the study in order to ensure that harm

is minimised and benefits maximised for the study subjects: an interim trial data analysis to compare the

efficacy of the two regimens will be performed after 50% of the subjects have been enrolled for more than one

month, or if 10 participants in the darunavir arm fail; the DSMB will issue recommendations concerning trial

continuation. Membership of the DSMB will be completely independent of the study staff.

Stopping rules:

All participants with detectable viral loads (>50 copies/mL) will receive adherence counselling, with a repeat

test at 1 month. If detectable ≥200 copies/mL, a resistance test will be performed, and the participant terminated

from the study. Darunavir toxicity will be managed according to the PI’s discretion, and carefully documented.

Pregnancy will not be a reason for termination on the study, although women who elect to stay in the study on

the DRV arm will have their darunavir dose escalated to 800mg.

End-of-Study Visit/Early withdrawal: An end-of-study visit will occur either at the end of the study (Week

48) or earlier if the participant withdraws from the study. During the end-of-study visit, clinical assessments,

blood sampling, AE and concomitant medication monitoring will be conducted.

Efficacy Assessments: Efficacy will be assessed by the evaluation of plasma HIV-1 RNA (primary measure of

efficacy).

Primary Endpoint: The primary efficacy endpoint will be the proportion of participants with undetectable

plasma HIV-1 RNA levels (<50 copies/mL) at Week 48. Participants who do not have a HIV-1 RNA sample

taken at Week 48 will be considered as not having achieved undetectable plasma HIV-1 RNA levels

(<50 copies/mL) at Week 48.

Secondary Endpoints:

Efficacy

Time to virologic failure (defined as confirmed HIV-1 RNA levels ≥200 copies/mL)

Safety

Change in lipids measured at Baseline, 24, and 48

Change in fasting glucose at Baseline and 48

Creatinine clearance (Cockcroft-Gault formula) at Baseline, 12, 24 and 48

AST/ALT at Baseline, 12, 24 and 48

Safety Assessments: Safety analysis will be performed by presenting data on physical examination, vital sign

measurements, clinical laboratory analyses and monitoring AEs and concomitant medications throughout the

study.


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Study Medication, Dosage, and Route of Administration

Treatment Group 1: Darunavir (DRV; 400 mg QD) plus ritonavir (RTV; 100 mg QD) administered in

combination with 2 N(t)RTIs orally over 48weeks

Treatment Group 2: Lopinavir (LPV; total dose 800 mg/day) plus ritonavir (RTV; total dose 200 mg/day)

administered in combination with 2 N(t)RTIs orally over 48 weeks

Sample Size: 300 participants randomly assigned in a 1:1 ratio (approximately 150 participants per treatment

group).

Statistical Methods: We anticipate a low loss to follow-up, of around 10-20%. We intend to randomise 150

participants to each arm, and follow them up over the period of one year. A sample size of 150 participants per

arm (300 total) would provide over 80% power to establish non-inferior efficacy for the DRV/r arm, compared

to the LPV/r arm. This calculation assumes that at least 80% of participants in the LPV/r arm maintain HIV-

RNA suppression at the end of the study. This calculation also assumes an overall 5% significance level (two

one-sided tests). All data, where applicable, will be summarised by treatment group using descriptive statistics.

Analysis Sets

All-Randomised Set: The all-randomised set will consist of all randomised participants, regardless of whether

or not any study treatment dosing was completed. Participants will be analysed according to the treatment they

were randomly assigned to.

Per-Protocol (PP) Set: The PP set will consist of all randomised participants who fully comply with the

inclusion and exclusion criteria, have received at least 80% of all doses of study treatment up to Week 48, and

have an evaluable plasma HIV-1 RNA level assessment at Week 48. Participants will be analysed according to

the treatment they received.

Safety Set: The safety set will consist of all participants who receive at least 1 dose of randomly assigned study

treatments. All safety analyses will be performed using the safety set. Participants will be analysed according to

the treatment they received.

Primary Efficacy Analyses: All efficacy analyses will be performed using the all-randomised and PP sets.

The difference in proportions of participants who achieve the primary endpoint between the 2 treatment groups

will be analysed using the binomial non-inferiority test for difference in proportions variable will also be

tabulated, displaying the proportions of participants with undetectable plasma HIV-1 RNA levels (with 95% CI)

by treatment group, the estimate (with 95% CI) for the difference in proportion between both treatment group

and the corresponding non-inferiority test P value. A 10% non-inferiority margin will be used.

Secondary Efficacy Analyses: No formal assessment of non-inferiority will be performed for any of the

secondary efficacy variables. Time to virologic failure will be analysed using a Cox proportional hazard model

with treatment as a factor. Change from baseline in plasma HIV-1 RNA levels and plasma CD4 levels will be

summarised by treatment group and visit.

Safety Analyses: Treatment emergent AEs will be tabulated by treatment, system organ class, seriousness,

severity, and relationship to treatment. Tabulations will contain the number and percentage of participants with

an event as well as the number of events. All AEs will be listed.

Shift tables (change from baseline value to on-treatment values) based on laboratory normal ranges will be

presented for each laboratory measurement at each assessment time. In addition, laboratory parameters will be

summarised by descriptive statistics.

Change in lipids, fasting glucose, creatinine clearance (Cockcroft-Gault formula), ALT and AST, clinical

laboratory parameters, vital sign measurements, physical examination data, previous and concomitant

treatments will be summarised by treatment group and visit, where relevant.

Date of Protocol: 26 October 2017


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1 Introduction

1.1 Background Information

Significant gains have been made in the last decade in terms of access to antiretroviral

care within developing countries through the support of local governments, international

donors, and agencies. However, as the number of participants on antiretroviral treatment

(ART) rises, there has been increased attention paid to treatment optimisation, whereby

drug dosage and manufacturing, clinical diagnosis and monitoring and health delivery

systems are all interrogated for increased efficiencies. Savings from these efforts can be

applied to treatment programmes, thus enabling more participants to receive life-saving

therapy. As antiretroviral drugs account for substantial cost within country human

immunodeficiency virus (HIV) treatment programmes, reducing costs associated with

individual medications would have a significant impact.

New, simpler, safer, more potent and potentially more cost-effective second line

antiretroviral therapy regimens are needed in South Africa. Some of the current second

line protease inhibitors that are routinely used in South Africa in both the public and

private sector have significant toxicity, limiting the durability of these regimens. There

is strong supportive evidence that darunavir, a protease inhibitor that can be dosed once

daily, with a significantly better side effect profile (better gastrointestinal profile, lower

impact on lipids) and greater resistance barrier compared to other protease inhibitors, can

have the dose halved from current levels. This will decrease the side effect profile further,

as well as reduce the cost of darunavir, as dose of drug is a major cost-driver for generic

manufacturers.

South Africa would hugely benefit from improved second line therapies, as it has the

largest number of people on antiretrovirals in the world. There are moves to improve first

line antiretroviral therapy further, by finding safer replacement drugs or reducing the

dose of currently used medication. However, even with better adherence with these

strategies, there will be a percentage of participants who will fail first line treatment.

Even using a very conservative 2% failure rate annually, this translates into around 10

000 participants transitioning to second line every year. A percentage of these, in turn,

will transition to the newly available South African third line regimens within the state

sector, which are an estimated 800% more expensive. Finding a second line regimen that

is more durable will limit transition to third line, protecting this class of drugs, and

limiting expense.

Decreasing total drug doses of antiretroviral agents, while maintaining efficacy,

represents an untapped possibility for decreasing costs and toxicity, if efficacy can be


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maintained. Manufacturing costs for originator companies comprise only a tiny part of

the price of the drug. However, with the rise of generic manufacturers, as well as

increased licensing by innovator companies to other pharmaceutical companies, the cost

of raw materials to manufacture the drugs (active product ingredient) have become a

more significant component of cost as prices have decreased. Thus, a dose reduction

could have a notable impact on the overall cost of ART.

1.2 Current Therapy

Access to antiretroviral therapy (ART) has expanded rapidly within South Africa, with

over 2.5 million participants initiated on therapy since 2004, with early suggestions of

resultant increase in life expectancy and even decreased incidence1, 2. The state

programme has, since its inception, used the WHO-recommended combination of two

nucleoside reverse transcriptase inhibitors (NRTIs) and a non-nucleoside reverse

transcriptase inhibitor (NNRTIs), a combination that demonstrates excellent virological

suppression with good adherence. With the update in WHO and South African National

Department of Health Guidelines in 2014, South Africa has moved towards fixed dose

combinations of 2NRTIs and an NNRTI, with implications for individual participants,

especially concerning adherence, as well as implications at programme level.

However, the combination has a low resistance barrier and poor adherence invariably

results in virological failure. Data on the number of first line failures in South Africa is

still elusive but a study looking at several programmes suggested just over 2% of

participants migrate across to second line annually (a larger percentage are lost to follow-

up)3. There is speculation that this percentage will rise, as programmes get larger and

adherence counselling is spread across more participants4.

The South African programme uses two nucleoside reverse transcriptase inhibitors and a

booster protease inhibitor (PI), LPV/r, as its second line regimen for virological failures

on first line, with boosted atazanavir (ATV) recently becoming available for participants

intolerant to LPV/r5. However, intolerance to boosted protease inhibitors is well

described, and includes gastrointestinal and metabolic concerns. Recently, in response to

a growing number of participants failing second line therapy, third line drugs including

darunavir, raltegravir and etravirine, as well as genotype resistance testing, have been

made available within the South African state programme, and overseen by an expert

committee5.

First line failures are almost always due to adherence problems; current second line

adherence is invariably even more difficult, due to a higher pill burden, twice daily dosing

and greater toxicity7. Provision of a better tolerated second line, with a higher resistance


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barrier and simplified dosing, would be a major advance in the provision of antiretroviral

care, for the accumulating participants on second line8.

1.3 Rationale

Dose finding of many currently licensed antiretrovirals was through identification of the

maximum tolerated dose that resulted in virological suppression, with the pharmaceutical

company’s focus on optimising the chance of success for that individual drug. Thus, dose

reduction was generally driven by toxicity, rather than virological suppression efficacy.

Darunavir is a second generation protease inhibitor, first licensed in 2006 by the Food

and Drug Administration and in South Africa in 2010. As with all protease inhibitors in

current use, it is routinely ‘boosted’ with ritonavir. While some international guidelines

allow for protease inhibitors to be prescribed in first line, WHO and South African

guidelines have reserved this class of drug for participants who virologically fail or

cannot tolerate non-nucleoside reverse transcriptase-based first line regimens9. DRV/r

was regarded as a major advance in developed countries, as it offered a formidable

resistance barrier in groups of participants who had been heavily pre-treated with sub-

optimal regimens, including protease inhibitor-based regimens. The POWER and TITAN

darunavir registration studies examined the outcomes of participants with resistant virus,

many of whom presented with advanced disease, and demonstrated benefit over other

protease inhibitors in terms of efficacy. It is estimated that 11 mutations are required to

develop resistance to DRV/r, far more than the two other commonly used protease

inhibitors, lopinavir and atazanavir10.

Importantly, the dose of darunavir was obtained largely from treatment-experienced

participants with at least one darunavir mutation. Healthy volunteer studies showed no

short-term difference in a 400mg/100mg dose versus a 600mg/200mg dose11. In 2 PK

studies in HIV-positive people, halving the 800mg dose resulted in a 37% AUC reduction,

but all participants retained blood levels above the EC50 range12, 13. The initial dose

ranging treatment studies on DRV/r (POWER 1 and POWER 2) showed that 600/100mg

twice daily was the optimal dose, and this was selected going forward12. However, the

study included 400mg/100mg twice daily and daily arms; participants who had no PI

mutations did as well in these arms as the 600mg/100mg arm15, 16. Subsequent studies,

including the ARTEMIS and ODIN studies, showed no correlation between PK levels

and virological suppression, at different doses17, 18.

Darunavir can be dosed daily, if there are less than three darunavir-specific mutations.

For the South African programme, most participants transition to a twice-daily

zidovudine-containing regimen; this is currently not a substantial gain over the twice a


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day LPV/r combination. However, in future, there is the possibility that darunavir will be

combined with the once-daily dolutegravir, and studies are being designed to see if this

potentially potent, safe and once daily regimen will be an effective alternative to the

current twice-daily second line regimens.

DRV/r has traditionally not been considered as a substitute for the LPV/r or

atazanavir/ritonavir combination, due to its cost, even if it is highly discounted in South

Africa. However, at the CADO-2 meeting, (attended by the principal investigator for this

study), which evaluated potential future directions for drug development, identified that

the dose of this drug may be reduced from the current 800mg daily dose, to potentially

400 mg daily. This, with the Clinton Healthcare (CHAI) projected cost-savings if

volumes are attained, would mean that low dose DRV/r would be slightly cheaper than

conventional protease inhibitor formulations ($200/year, as opposed to $250 for

atazanavir/ritonavir and $300 for LPV/r). Subsequent communication at the end of 2014

with the originator company suggests that further price reductions than these, will be

possible with altered synthetic processes.

If it could be shown that the lower dose DRV/r was as virologically effective as LPV/r,

and had lower toxicity than LPV/r, this would decrease costs significantly, allowing

poorer countries, and potentially even richer countries, to continue use of this drug in

first line regimens. This study aims to demonstrate the non-inferiority of a lower dose of

DRV/r compared to LPV/r over 1 year of therapy, in terms of virological efficacy.

This switch study will be conducted according to International Conference on

Harmonisation (ICH) harmonised tripartite guideline E6(R1): Good Clinical Practice

(GCP) guidelines to support potential future registration of the lower dose of DRV/r by

regulatory agencies and consideration by guideline-forming groups to change policy

recommendations. The efficacy and safety of either DRV/r (400/100 mg once daily [QD])

or LPV/r (total dose per day 800/200 mg) administered in combination with 2 N(t)RTIs

will be evaluated in participants with HIV-1 who are stable and virologically suppressed

on standard of care second line ART over 48 weeks. The route of administration, dose

regimen, and study population have been outlined in consideration of the package inserts

for the commercial products used in this study and the target population currently in

receipt of these medications as the standard of care and in consideration of relevant

regulatory guidance documents.

There are several generic drug manufacturers that have the capability to produce the

lower dose of darunavir. CHAI will assist in securing a quality generic product, including


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negotiating entry into South Africa, in the event of international manufacture. The other

drugs in the regimens are commercially available locally, or will be provided by the local

Department of Health site.

Designed in non-inferiority fashion, this study will enrol approximately 300 participants

for 80% power to detect a 10% non-inferiority margin in the per-protocol (PP) analysis.

Robust safety analyses are included in the study design to enable the detection of adverse

events (AEs) at an early and reversible stage.

1.4 Other Study Medications

Participants will continue to receive the 2 N(t)RTI backbone drugs that they were on at

the time of screening. These will vary according to which N(t)RTI backbone they

received in the failed first line ART regimen. Women who become pregnant on the

darunavir arm and elect to stay in the study will have their darunavir dose escalated to

800mg. Refer to the package inserts of these drugs for further information on the

respective safety profiles.

2 Study Objectives

2.1 Primary Objective

The primary objective of this study is to assess the non-inferiority of DRV/r

400mg/100mg daily when compared with LPV/r total dose 800mg/200mg per day in

combination with a nucleoside backbone, as determined by the proportion of participants

on each regimen with undetectable plasma HIV-1 RNA levels (<50 copies/mL) at week

48.

2.2 Secondary Objective

The secondary objective of this study is to assess the tolerability and safety of low dose

DRV/r when switching from LPV/r, over 48 weeks, in participants infected with HIV-1

who are virologically suppressed and stable on standard second line therapy.

3 Study Design

This is an open label, randomised, parallel-group, phase 3b, single-site switch study. The

study includes a screening period (Days –60 to –1), an enrolment visit (Week 0), and a

48-week treatment period. The study design is displayed in figure 1.


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Screening and

Re-screening

Days -60 to -1

Treatment Group 1

DRV/r + 2 N(t)RTIs

Treatment Group 2

LPV/r + 2 N(t)RTIs

Enrolment

(Week 0)

Randomisation

Visit 1

(Week 4)

Visit 2

(Week 12)

Visit 3

(Week 24)

Visit 4

(Week 36)

End of

study visit

(Week 48)

EOS

Figure 1 Study design

Three hundred male and female participants infected with HIV-1 who are on standard of

care second line antiretroviral therapy (ART), with plasma HIV-1 RNA levels <50

copies/mL, will be randomly assigned in a 1:1 ratio (approximately 150 participants per

treatment group) to either Treatment Group 1 (low dose DRV/r + 2 N(t)RTIs) or

Treatment Group 2 (continuing existing LPV/r regimen + 2 N(t)RTIs), as shown in table

1. The randomisation will be electronically generated (using www.randomization.com)

and the site pharmacist will manage a system of manual envelopes. All medications will

be administered in an open label design.

All participants will be assigned a unique participant number by the randomisation

system. After a participant number has been assigned, the number will not be reused even

if the participant withdraws before receiving any study medication.

Table 1 Treatment Regimen

Study Medications Tablet/Capsule Strength Dosage Regimen

Treatment Group 1

DRV/r 400/100 mg Once daily

2 N(t)RTIs Depends on participant’s regimen Once or twice daily

Treatment Group 2

LPV/r 800/200 mg Total dose per day

2 N(t)RTIs Depends on participant’s regimen Once or twice daily

Abbreviations: DRV/r, boosted darunavir; N(t)RTIs, nucleoside/nucleotide reverse transcriptase inhibitors;

LPV/r, boosted lopinavir.

4 Selection of Study Population

http://www.randomization.com/


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Three hundred participants infected with HIV-1 who are on standard of care second line

antiretroviral therapy (ART), with plasma HIV-1 RNA levels <50 copies/mL, will be

considered for enrolment in the study if they meet all of the inclusion criteria and none

of the exclusion criteria.

Before performing any study procedures, all potential participants will provide written

informed consent, and will sign an informed consent form (ICF). Participants will have

the opportunity to have any questions answered before signing the ICF. The informed

consent process and all questions raised by the participant must be documented. The

study staff will also sign the ICF.

4.1 Inclusion Criteria

Each participant must meet all of the following criteria to be enrolled in this study:

1) Participant is aged ≥18 years

2) Participant weight >40kg

3) Participant is on a LPV/r-containing regimen for more than 6 months with no

history of other protease inhibitors

4) Participant has a plasma HIV-1 RNA level <50 copies/mL within 60 days

5) Participant is informed and has the ability to comprehend the full nature and

purpose of the study, and give voluntary informed written consent before

inclusion in the study

4.2 Exclusion Criteria:

Participants meeting any of the following criteria will be excluded from the study:

1) Participants who are taking any antiretrovirals other than nucleoside/nucleotide

reverse transcriptase inhibitors and LPV/r

2) Any prior history of genotype-documented protease inhibitor resistance

3) Participants who are taking rifampicin or any other therapy with major

cytochrome P450 interactions within last month

4) Participants who are allergic to sulphonamides

5) Participants who have a current history of drug or alcohol abuse that, in the

opinion of the investigator, may be an impediment to participant adherence to

the protocol

6) Female participants who are currently pregnant or breastfeeding

7) Female participants desiring pregnancy during the next year

8) Participants who have a strong likelihood of relocating far enough to make

access to the study site difficult


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9) Any condition(s) or laboratory report that, in the opinion of the investigator,

might put the participant at risk, or interfere with the study objectives or the

participant’s adherence to study requirements

5 Study Procedures

Refer to Schedule of Events (Table 3)

5.1 Screening:

1) Informed consent process

2) Confirm HIV-1 status

3) Demography data

4) Pre-existing medical condition(s)

5) Physical examination, height, weight and vital sign measurements

6) Urine pregnancy test

7) Concomitant medications

8) Clinical laboratory testing:

Full blood count

HIV-1 RNA

CD4 count

Hepatitis B surface antigen test (HBsAg)

Alanine amino transaminase (ALT) and Aspartate aminotransferase (AST)

Creatinine and calculated clearance

Lipid panel

9) Inclusion/exclusion criteria determination

Re-Screening (Days -60 to -1)

During the 60-day screening period, a participant may be re-screened to determine

eligibility. Re-screening will involve retesting of subsequent biological samples,

and/or re-assessment of any inclusion and exclusion criteria that previously failed the

participant.

5.2 Enrolment:

1) Review inclusion/exclusion criteria

2) Review pre-existing medical condition(s)

3) Symptom-led physical examination

4) Weight measurement

5) Blood pressure measurement


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7) Fasting plasma glucose


9) Clinical laboratory testing as necessary

10) Randomisation

11) Study medications dispensing and patient education

12) Study medication accountability

13) Monitor adverse event

5.3 Follow-up visit procedure:

1) Assess adverse events


3) Physical examination at end of study visit and symptom-led at other visits

4) Weight and blood pressure measurement


6) Clinical laboratory testing:

Plasma HIV-1 RNA (week 12, 24, 36 and 48)

CD4 count (Week 48)

Haemoglobin (Week 12, 24, 36); Full blood count (Week 48)

Creatinine (Week 12, 24 and 48)

Alanine amino transaminase (ALT) and Aspartate aminotransferase (AST)

(Week 12, 24 and 48)

Lipids (Week 24 and 48)

Glucose (Week 48)

7) Study medications dispensing and patient education

5.4 Efficacy Assessments

Efficacy will be assessed by the evaluation of plasma HIV-1 RNA level. The primary

efficacy endpoint will be the proportion of participants with undetectable plasma HIV-1

RNA levels (<50 copies/mL) at Week 48. Participants who do not have a HIV-1 RNA

sample taken at Week 48 will be considered as not having achieved undetectable plasma

HIV-1 RNA levels (<50 copies/mL) at Week 48.

All participants with detectable HIV-1 RNA (>50 copies/mL) will receive adherence

counselling, with a repeat test at 1 month from the date of counseling. If repeated HIV-1

RNA ≥200 copies/mL, a resistance test will be performed, and the participant terminated

from the study. In instances where HIV-1 RNA copies cannot be amplified, investigator’s

discretion will apply.


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5.5 Early withdrawal

Participants are free to withdraw from the study at any time for any reason. If a participant

withdraws from the study early, all procedures for the end-of-study visit should be

conducted. The investigator may also withdraw the participant at any time in the interest

of participant safety or if the study is terminated. The primary reason for withdrawal must

be recorded in the source document.

Participants who fail to return for final assessments will be contacted by the site in an

attempt to have them comply with the protocol. At least 2 attempts (by telephone,

personal visit, or e-mail) will be made before the participant is considered lost to follow-

up. All follow-up attempts (method, date, and time) must be documented in the source

document.

The investigator may withdraw a participant from the study if the participant:

Is in violation of the protocol

Experiences a serious or intolerable AE which interferes with study procedures

Has laboratory safety assessments that reveal clinically significant changes from

the baseline values

Experiences virological failure

Requires a medication that is prohibited by the protocol

Consent is withdrawn or the participant refuses to continue participation and/or

procedures/observations

A participant can also be withdrawn at the discretion of the investigator.

5.6 Replacements

Participants who discontinue participation in the study for any reason after randomisation

will not be replaced.

6 Safety Assessments

Safety evaluations will include the monitoring of AEs and concomitant medications,

clinical laboratory assessments, physical examinations, vital sign measurements, and

evaluation of changes in lipids, fasting glucose, ALT, AST and creatinine clearance.

Safety issues will be discussed in detail among study doctors and with the participant

before taking any decisions.

6.1 Adverse Events

An AE is defined as any untoward medical occurrence in a participant in a clinical

investigation with a medicinal product regardless of its causal relationship to study

medication. Participants will be instructed to contact the principal investigator or

designee at any time after randomisation if any symptoms develop.


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A treatment-emergent AE is defined as any event, including laboratory abnormalities, not

present before exposure to study medication or any event already present that worsens in

either intensity or frequency after exposure to study medication.

An AE is also any of the following occurring after study randomisation:

Complications that occur as a result of a protocol-mandated procedure after

randomisation to study medications

Any pre-existing condition that increases in severity or changes in nature during

or as a consequence of the study after randomisation to study medications

Reasons for and complications arising from a termination of pregnancy due to

medical and/or surgical reasons

An AE does not include the following:

Medical or surgical procedures performed. However, the condition that leads to

the procedure is an AE

Pre-existing diseases or conditions or laboratory abnormalities present or

detected before screening visit that do not get worse

Situations where an untoward medical occurrence has not occurred (e.g.

hospitalisation for elective surgery)

Overdose without clinical sequelae

Uncomplicated pregnancy

An induced elective abortion to terminate a pregnancy without medical reason

Adverse events will be assessed (reported and/or observed) and documented from

enrolment once the participant is randomised to study medications, until exit from the

study (i.e. early withdrawal or end-of-study visit at week 48). Any medical conditions

observed at screening and which do not exclude the participant from the study will be

documented as pre-existing medical conditions. All AEs will be followed to adequate

resolution. Any ongoing AE at early withdrawal or the end-of-study visit will be further

followed until satisfactory resolution or until the investigator deems the event to be

chronic or the participant to be stable, up to a maximum of 30 days after the last visit.

AEs will be documented in chart notes and those of grade 3 and 4 and unexpected ADR

will be entered into the AE CRF.

6.2 Serious Adverse Events

An SAE is defined as any AE that:

Results in death


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Is immediately life threatening (includes events which put participants at risk of

death at the time of the event but not events which may have caused participant

death if more severe)

Requires in-patient hospitalisation or prolongation of existing hospitalisation

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Of clinical significance in the opinion of the investigator

Any SAE must be documented in an SAE CRF. All SAEs and unexpected ADRs will be

reported to the Wits RHI Safety Committee (WSC), by email, within 24 hours from the

time site personnel first learn of the event.

6.3 Assessment of AEs

The severity or intensity of an AE refers to the extent to which an AE affects the

participant’s daily activities. The severity of all AEs, including laboratory

abnormalities, will be graded according to the Division of AIDS grading table (version

2.0, November 2014).

The relationship or association of the study medication in causing or contributing to the

AE will be characterised using the following classification and criteria:

Unrelated: This relationship suggests that there is no association between the study

medication and the reported event.

Related: This relationship suggests that a definite causal relationship exists between drug

administration and the AE, and other conditions (concurrent illness,

progression/expression of disease state, or concurrent medication reaction) do

not appear to explain the event.

All SAEs that occur during the study (regardless of relationship to study medication)

must be reported in detail and followed until the events resolve, stabilise, or become

nonserious. All SAEs will be reported to HREC according to HREC requirements.

Medical and scientific judgement should be exercised in deciding whether an AE, which

does not meet the routine definition of an SAE but is important from a safety perspective

and may jeopardise the participant or require intervention to prevent one of the other

outcomes listed in the definition of serious, should be considered as serious.

6.5 Management of Pregnancy

A urine pregnancy test will be performed in all female participants of childbearing

potential at every visit from screening to the end-of-study (Week 48)/early withdrawal

visit, and as required during the study according to local standard practice for clinical


Page 23

care or according to the investigator’s discretion, where pregnancy may be suspected.

All pregnant women will be followed until post-partum, and children will be followed to

6 months; these follow-ups can only be done during study lifecycle. . If a woman

becomes pregnant during the study and consents to further participation, they may elect

to remain in the study. Women on darunavir will have their DRV dose doubled for the

duration of the pregnancy. Any women who become pregnant during the study will be

fully counselled on the risks. Both darunavir and lopinavir are assigned to pregnancy

category C by the US Food and Drug Administration, which indicates that risk cannot be

ruled out. Nonclinical studies do not indicate direct or indirect harmful effects with

respect to pregnancy but no well-controlled studies have been performed in pregnant

women.

6.6 Physical Examination and Vital Sign Measurements

A physical examination will be performed at screening, and where clinically indicated

thereafter. Height and weight will be recorded at the screening visit and weight will be

measured at all clinic visits from baseline to the end-of-treatment (Week 48)/early

withdrawal visits, inclusive.

Vital sign measurements (temperature, pulse rate, systolic and diastolic blood pressure)

will be collected at screening. At all other study visits only blood pressure will be

measured and other vital signs only if indicated.

7 Study Treatments

All study medications (Table 2) are to be orally self-administered as directed according

to the package insert. Open label study medication will be supplied to the participant at

enrolment and Week 4 - 36. All medications used in this study will be provided as open-

label medications. Participants will be instructed to bring all used and unused study

medication bottles with them to each study visit.


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Table 2 Study Medication Supplies

Product Formulation Manufacturer

Darunavir 400 mg tablets Hetero Drugs Ltd, India

Ritonavir 100 mg tablets Hetero Drugs Ltd, India

Lopinavir/ritonavir

(FDC) 400/100 mg tablets Abbott Laboratories/Abbvie

N(t)RTIs Depends on participant’s

regimen

Depends on participant’s

regimen

Abbreviations: FDC, fixed dose combination; N(t)RTIs, nucleoside/nucleotide reverse

transcriptase inhibitors

Darunavir

Darunavir tablets will be manufactured and supplied by Hetero Drugs Limited, India.

Each tablet contains darunavir ethanolate equivalent to 400mg of darunavir. The tablet

is an orange, oval shaped, bevel edged, biconvex, film coated tablet de-bossed with “H”

on one side and “189” on the reverse side. The tablets will be stored at 25°C (77°F); with

excursions permitted to 15°-30°C (59°-86°F).

Ritonavir

Ritonavir tablets will be manufactured and supplied by Hetero Drugs Limited, India.

Each tablet contains 100mg of ritonavir. Ritonavir will be supplied as white to off white,

capsule shaped, film coated tablets debossed with H on one side and R9 on other side.

The medication will be stored at 25°C (77°F); with excursions permitted to 15°-30°C

(59°-86°F).

Lopinavir/ritonavir

Lopinavir/ritonavir tablets are a co-formulation of 200mg lopinavir and 50mg ritonavir

as a film-coated tablet. The medication is packed in a white plastic bottle of 112 tablets,

and will be stored at room temperature (below 30 0C).

N(t)RTIs

Consult package insert of appropriate drug.

All study medications will be stored per manufacturer’s specifications in the package

insert.

7.1 Medication Supplies

The study site will acquire study medication from commercial suppliers. All study

medications will be administered in an unblinded fashion and supplied as commercial


Page 25

drug, over-labelled for clinical trial use in accordance with local regulatory requirements.

At the site, all study medications must be kept in a secure cabinet or room with access

restricted to only necessary study site personnel. Storage instructions for site personnel

and participants will be provided on the label. Study medication labels will contain

information to meet the applicable regulatory requirements.

7.2 Study Medication Accountability

The investigator will maintain accurate records of receipt of all study medications,

including dates of receipt. In addition, accurate records will be kept regarding when and

how much study medication is dispensed and used by each participant in the study. At

the completion of the study, to satisfy regulatory requirements regarding drug

accountability, all study medications will be reconciled and retained or destroyed

according to applicable regulations. Participant compliance will be evaluated through

review of drug dispensing and administration records.

7.3 Prior, Concomitant and Subsequent Therapy

Protease inhibitors are known to have varying effects on cytochrome P450 (CYP)3A,

with the major effect being inhibition. Co-administration of PIs with drugs primarily

metabolised by these isozymes may result in altered plasma concentrations of the co-

administered drug and of the PI, and interactions may be hard to predict. Therefore,

appropriate dose adjustments may be necessary for these drugs. Drugs that induce

CYP3A activity (e.g. phenobarbital, rifampicin, rifabutin) would be expected to increase

the clearance of PIs resulting in lowered plasma concentrations.

Any drugs with significant interactions with cytochrome P450 enzymes will be

discouraged, or used as an exclusion criterion. Use of all concomitant medications will

be recorded in the participant’s CRF. This will include all prescription drugs, herbal

products, vitamins, minerals, and over-the-counter medications.

7.4 Process for Antiretroviral Switch

In certain cases, including but not limited to drug toxicity and/or pregnancy, substitution

of NRTIs with an alternate antiretroviral per standard of care is permissible at the

investigator’s discretion.


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7.5 Post-trial access to darunavir 400mg

Darunavir/ritonavir 400mg/100mg will be provided to study participants if not available

in the public sector. Post-trial access will be limited to patients who were randomised and

received this study drug up to the end-of-study visit (week 48). In the event that

darunavir/ritonavir 400mg/100mg is not available, darunavir/ritonavir 600mg/100mg

once daily will be provided as post-trial access in the interim until the usual stock of

darunavir/ritonavir 400mg/100mg becomes available at the study site or government

provision of darunavir has commenced in the public sector. Post-trial access will be

conducted according to Table 4, section 11 of this protocol.

8 Statistical Analysis Plans

8.1 Primary Efficacy Endpoint

The primary efficacy endpoint is the proportion of participants with undetectable plasma

HIV-1 RNA levels (<50 copies/mL) at Week 48. Participants who do not have a HIV-1

RNA sample taken at Week 48 will be considered as not having achieved undetectable

plasma HIV-1 RNA levels (<50 copies/mL) at Week 48.

8.2 Secondary Efficacy Endpoints

The secondary efficacy endpoints are as follows:

Time to virologic failure (defined as confirmed HIV-1 RNA levels ≥200

copies/mL at any visit)

Change from baseline in plasma HIV-1 RNA levels by visit

8.3 Safety Endpoints

The primary safety endpoint is the assessment of the tolerability and safety of low dose

DRV/r as measured by the nature and frequency of AEs and changes in vital sign

measurements, physical examination findings, and clinical laboratory analyses.

Secondary safety endpoints are as follows:

Change in lipids measured at Baseline, 24 and 48

Fasting glucose at Baseline and 48

Creatinine clearance (Cockcroft-Gault formula) at Baseline, 12, 24, 36 and 48

8.4 Sample Size Calculations

A total of 300 male and female participants infected with HIV-1 who are virologically

suppressed and stable on a standard of care second line regimen will be randomised in a


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1:1 ratio (150 participants per treatment group) to Treatment Group 1 (DRV/r + 2

N(t)RTIs) or Treatment Group 2 (LPVV/r + 2 N(t)RTIs). Participants are stable on

treatment. We anticipate a low loss to follow-up, of around 10-20%. We intend to

randomise 150 participants to each arm, over a year period, and follow them over a year.

A sample size of 150 participants per arm (300 total) would provide over 80% power to

establish non-inferior efficacy for the DRV/r arm, compared to the LPV/r arm. This

calculation assumes that at least 80% of participants in the LPV/r arm maintain HIV RNA

suppression at the end of the study. This calculation also assumes an overall 5%

significance level (two one-sided tests). All data, where applicable, will be summarised

by treatment group using descriptive statistics.

8.5 Analysis Sets

The following analysis sets will be used in the statistical analyses:

All-randomised set: The all-randomised set will consist of all randomised participants,

regardless of whether or not any study treatment dosing was completed. Participants will

be analysed according to the treatment they were randomly assigned to.

Per-protocol set: The PP set will consist of all randomised participants who fully comply

with the inclusion and exclusion criteria, have received at least 80% of all doses of study

treatment up to Week 48, and have an evaluable plasma HIV-1 RNA level assessment at

Week 48. Criteria will be defined in more detail in the statistical analysis plan (SAP).

Participants will be analysed according to the treatment they received.

Safety set: The safety set will consist of all participants who receive at least 1 dose of

randomly assigned study treatments. All safety analyses will be performed using the

safety set. Participants will be analysed according to the treatment they received.

All efficacy analyses will be performed using the all-randomised and PP sets. All safety

analyses will be performed using the safety set.

8.6 Statistical Analysis

Where applicable, the calculation also assumes an overall 5% significance level (two

one-sided tests). All data, where applicable, will be summarised by treatment group using

descriptive statistics. Continuous variables will be summarised by number of participants,

the mean, standard deviation, the median, the minimum value, and the maximum value.

Categorical variables will be summarised using frequency counts and percentages. All

data collected will be listed. Baseline will be defined as the last measurement before first


Page 28

intake of randomised study treatment. Further details on the statistical analysis

methodology will be provided in the SAP.

Missing data for the primary efficacy endpoint will be handled as per Section 0.

Sensitivity analyses will be performed to assess the impact of missing data on the

interpretation of the results, and further details will be provided in the SAP.

8.7 Primary Efficacy Analysis

The primary endpoint is the proportion of participants with undetectable plasma HIV-1

RNA levels (<50 copies/mL) at Week 48.

The difference in proportions of participants who achieve the primary endpoint between

the 2 treatment groups will be analysed. This variable will also be tabulated, displaying

the proportions of participants with undetectable plasma HIV-1 RNA levels (with 95%

CI) by treatment group, the estimate (with 95% CI) for the difference in proportion

between both treatment groups, and the corresponding non-inferiority test P value.

This non-inferiority study has been powered based on a non-inferiority margin of 10%.

This is the lowest, most conservative difference that has been found most useful when

comparing 1 component of a 3-drug regimen in treatment-naive individuals. The actively

compared treatments in this study are low-dose DRV/r and LPV/r. Assessing the

outcome of the trial using the 10% non-inferiority margin will determine if low-dose

DRV/r is, at worse, 10% below that of standard doses of LPV/r with regards to plasma

HIV-1 RNA levels at Week 48.

The consistency of the treatment effect across subgroups will be investigated. All efficacy

analyses will be performed using the all-randomised and PP sets.

8.9 Safety Analyses

Treatment-emergent AEs will be tabulated by treatment, system organ class, preferred

term, seriousness, severity, and relationship to treatment. Tabulations will contain the

number and percentage of participants with an event as well as the number of events. All

AEs will be listed.

Shift tables (change from baseline value to on-treatment values) based on laboratory

normal ranges will be presented for each laboratory measurement at each assessment

time. In addition, laboratory parameters will be summarised by descriptive statistics.

Change in lipids, fasting glucose and creatinine clearance (Cockcroft-Gault formula),

clinical laboratory parameters, vital sign measurements, physical examination data,


Page 29

previous and concomitant treatments, and medical history will be summarised by

treatment group and visit, where relevant.

8.10 Interim Analyses

A data safety monitoring board (DSMB) will monitor the study in order to ensure that

harm is minimised and benefits maximised for the study subjects. Membership of the

DSMB will be completely independent of the study staff.

An interim trial data analysis to compare the efficacy of the two regimens will be

performed after 50% of the subjects have been enrolled for more than one month, or if

10 participants in the darunavir arm fail; the DSMB will issue recommendations

concerning trial continuation.

Stopping rules:

All participants with detectable viral loads will receive adherence counselling, with a

repeat test at 1 month. If persistently detectable above 200 copies/mL, a resistance test

will be performed, and the participant terminated from the study. Darunavir toxicity will

be managed according to the PI’s discretion, and carefully documented. Pregnancy will

not be a reason for termination on the study. No formal stopping rules will be used by the

DSMB for safety outcomes. The DSMB will provide an independent clinical assessment

to determine if lack of efficacy on low dose DRV/r warrants the early termination of the

study in the best interest of the participants.

9 Data Management

At every visit, participants’ information will be recorded in source documents including

chart notes and laboratory test results. Data from CRFs and other data sources will be

entered into an electronic database as specified in the data management SOP. Quality

control and data validation procedures will be applied to ensure the validity and accuracy

of the data. The electronic database will be designed in REDCap (REDCap Software -

Version 6.2.5 - © 2015 Vanderbilt University).

Each person involved with the study will have an individual logon and password that

allows for record traceability. Thus, the system, and subsequently any investigative

reviews, can identify coordinators, investigators, and individuals who have entered or

modified records.

http://projectredcap.org/


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10 Other study Activities

10.1 Confidentiality

All laboratory specimens, evaluation forms, reports, and other records will be identified

in a manner designed to maintain participant confidentiality. All records will be kept in a

secure storage area with limited access. Clinical information will not be released without

the written permission of the participant, except as necessary for monitoring and auditing

by the regulatory authorities or the HREC.

The principal investigator or designee and all employees and co-workers involved with

this study may not disclose or use for any purpose other than performance of the study,

any data, record, or other unpublished confidential information disclosed to those

individuals for the purpose of the study. All computers are password-protected and

records can only be accessed by permitted study staff.

10.2 Reporting

The protocol and relevant supporting documents must be submitted to the Medicine

Control Council (MCC) and HREC for approval. The study protocol will be registered

with the South African National Clinical Trial Registry (www.sanctr.gov.za)/ National

Human Research Ethics Committee (www.ethicsapp.co.za) and the ClinicalTrial.gov.

Six monthly progress reports will be submitted to MCC and HREC for the duration of

the study. Annual recertification will be obtained from HREC. Upon completion or

premature termination of the study, the investigator will provide HREC with a summary

of the study’s outcome, and the regulatory authorities with any reports required.

10.3 Investigator Documentation

Prior to beginning the study, the principal investigator will be asked to comply with ICH

E6(R1) 8.2 by providing the following essential documents, including but not limited to:

An original investigator-signed investigator agreement page of the protocol

An HREC-approved ICF, samples of site advertisements for recruitment for this

study, and any other written information regarding this study that is to be provided

to the participants

HREC approval

Curriculum vitae for the principal investigator and each investigator. Current

licensure must be noted on the curriculum vitae. They will be signed and dated

by each investigator at study start-up, indicating that they are accurate and current

Laboratory certifications and normal ranges for any local laboratories used by the

site

http://www.sanctr.gov.za/

http://www.ethicsapp.co.za/


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10.4 Monitoring of the Study

The study monitor has the obligation to follow the study closely. In doing so, the monitor

will visit the study facility at periodic intervals, in addition to maintaining necessary

telephone and email contact. The monitor will maintain current personal knowledge of

the study through observation, review of study records and source documentation, and

discussion of the conduct of the study with the principal investigator and study staff. All

aspects of the study will be carefully monitored for compliance with applicable

government regulation with respect to current ICH GCP guidelines and current standard

operating procedures.

10.5 Protocol Amendments

Amendments to the protocol must be submitted in writing to the MCC and HREC for

approval before participants are enrolled into an amended protocol, except where it is

necessary to eliminate an immediate hazard to participants or where the changes involve

only logistical or administrative aspects of the clinical study. This should be fully

documented.

10.6 Protocol Violations and Deviations

The principal investigator or designee must document and explain in the participant’s

source documentation any deviation from the approved protocol. The principal

investigator or designee may implement a deviation from, or a change of, the protocol to

eliminate an immediate hazard to trial participants without prior HREC approval. As

soon as possible after such an occurrence, the implemented deviation or change, the

reasons for it, and any proposed protocol amendments should be submitted to the HREC

for review and approval and to the regulatory authorities, if required.

A deviation from the protocol is an unintended or unanticipated departure from the

procedures or processes approved by the HREC and agreed to by the principal

investigator or designee. Deviations usually have an impact on individual participants or

a small group of participants and do not involve inclusion, exclusion or primary endpoint

criteria. A protocol violation occurs when there is nonadherence to the protocol that

results in a significant, additional risk to the participant, when the participant or principal

investigator or designee has failed to adhere to significant protocol requirements

(inclusion and exclusion criteria) and the participant was enrolled without prior approval,

or when there is nonadherence to regulations or some ICH GCP guidelines. Protocol

violations and deviations will be documented by the clinical monitor throughout the

course of monitoring visits. Principal investigators or designees will be notified in


Page 32

writing by the monitor of violations and deviations. The HREC should be notified of all

protocol violations and deviations in a timely manner.

10.7 Inspection of Records

Principal investigators or designee and institutions involved in the study will permit trial-

related monitoring, audits, HREC review, and regulatory inspections by providing direct

access to all study records.

10.8 Records Retention

All correspondence (e.g. with HREC, or MCC) relating to this clinical study should be

kept in appropriate study folders. Records of participants, source documents, CRFs, and

drug inventory sheet pertaining to the study must be kept on file. Essential documents

should be retained until at least 2 years after the last approval of a marketing application

in an ICH region and until there are no pending or contemplated marketing applications

in an ICH region or at least 2 years have elapsed since the formal discontinuation of

clinical development of the investigational product. These documents should be retained

for a longer period, if required by the applicable regulatory requirements. If an

investigator moves, withdraws from an investigation, or retires, the responsibility for

maintaining the records may be transferred to another person, who is willing to accept

the responsibility.

10.9 Study Termination

Although Wits RHI has every intention of completing the study, Wits RHI reserves the

right to discontinue the study at any time for clinical or administrative reasons. The end

of the study is defined as the date on which the last participant completes the last visit.

10.10 Publications

After completion of the study, the data may be considered for reporting at a scientific

meeting or for publication in a scientific journal. In these cases, the investigator will be

responsible for these activities and will determine how the manuscript is written and

edited, the number and order of authors, the publication(s) to which it will be submitted,

and other related issues according to the Wits RHI publication guidelines.


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11 Appendix: Schedule of Events

Table 3 Schedule of Events

Study Visit Baseline

Visit 1 Visit 2 Visit 3 Visit 4 Visit 5

/EOS Screening Enrolment

Study Week – 0 4 12 24 36 48

Study Day/Window –60 to –1 0 15-42 71–98 155–182 239–266 323–350

Informed consent X

Demography X

Medical history/pre-existing conditions X X

Urine pregnancy testing X X X X X X X

Physical examination1 X X X X X X X

Height measurement X

Weight measurement X X X X X X X

Vital sign measurements2 (BP, Temp, Res rate, Pulse) X X X X X X X

Hepatitis B antigen X

Creatinine clearance (Cockcroft-Gault formula) X X X X

Haemoglobin X X X

FBC X X

CD4 cell count X X

HIV ELISA (optional) X

Plasma HIV-1 RNA X X X X X

Fasting plasma glucose X X

Lipid panel X X X

AST/ALT X X X X

Previous/concomitant medications X X X X X X X

Inclusion/exclusion criteria X X

Randomisation X

Study medications dispensed X X X X X

Study treatment/medication accountability X X X X X X

Adverse event monitoring X X X X X X

1. Physical examination must be done at screening and EOS visit, but symptom-led at other visits.

2. Only blood pressure will be measured at visits: Baseline, 1, 2, 3 and 4; other vitals will be done only if indicated.


Page 34

Table 4 Schedule of Post-Trial Access

1 Quantity of medication dispensed is at pharmacist’s discretion

Study Visit Visit 6 Visit 7 Visit 8 Visit 9 Visit 10

Study Month 6 12 18 24 36

Study Month/Window ±2 weeks ±2 weeks ±2 weeks ±2 weeks ±2 weeks

Urine pregnancy testing X X X X X

Physical examination X X X X X

Weight measurement X X X X X

Vital sign measurements (BP, Temp, Res rate, Pulse) X X X X X

Creatinine clearance (Cockcroft-Gault formula) X X X X X

FBC (including Hg) X X X X X

CD4 cell count X X X X X

Plasma HIV-1 RNA X X X X X

Fasting plasma glucose X X X X X

Lipid panel X X X X X

AST/ALT X X X X X

Previous/concomitant medications X X X X X

Study medications dispensedi X X X X X

Study treatment/medication accountability X X X X X

Adverse event monitoring X X X X X


Page 35

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Documents

CLINICAL STUDY PROTOCOL - WRHI...CLINICAL STUDY PROTOCOL A randomised, open label switch study comparing darunavir/ritonavir 400mg/100mg daily with lopinavir/ritonavir 800mg/200mg